Various kinds of prostaglandins and various kinds of leukotrienes are produced in the bodies of mammals in response to variety of stimuli such as inflammatory stimuli and physical stimuli.
Both of prostaglandins and leukotrienes are metabolites of arachidonic acid, and they are physiologically active substances referred to as lipid mediators, and they cause various physiological responses of mammals by binding to receptors expressed on surfaces of various cells or in the cells.
Arachidonic acid is produced from a phospholipid as a substrate, such as phosphatidylcholine which is a cell membrane component, with the aid of an enzymatic activity of phospholipase A2 (PLA2).
Arachidonic acid produced by the action of PLA2 is converted into prostaglandin (PG) H2 with the aid of an enzymatic activity of constitutive type cyclooxygenase (COX) 1 or inducible type COX-2, and further converted into PGE2, PGD2, PGF2α, PGI2, thromboxane (TX) A2 and the like with the aid of each synthetic enzyme. Further, arachidonic acid is also metabolized by the action of 5-lipoxygenase (5-LO) and thereby converted to leukotriene (LT) A4, and further converted to LTB4, LTC4, LTD4, LTE4 and the like by the enzymatic activities of LTA4 hydrolase, LTC4 synthase, glutathione S-transferase and the like [Goodman & Gilman, Pharmacological Basis of Therapeutics, 9th edition, p. 801, 1999 (Hirokawa Shoten); Funk, C. D., SCIENCE, vol. 294, p. 1871, 2001].
Prostaglandins bind to each specific receptor to cause inflammatory reactions such as fervescence, enhancement of vascular permeability, vasodilation, swelling and pain, bronchial smooth muscle contraction, platelet aggregation, tumor cell proliferation, enhancement of bone resorption, nerve cell degeneration and the like, and thus play important roles in expression of symptoms or pathological formation for various diseases.
Leukotrienes are physiologically active substances which bind to each specific receptor to cause inflammatory reactions such as excessive accumulation of leucocytes and enhancement of vascular permeability, smooth muscle contraction, mucus secretion, proliferation of tumor cells and the like, and thus play important roles in expression of symptoms or pathological formation for various diseases.
Although inflammatory reactions themselves are essential reactions for living bodies to survive when they face pathogenic substances and affections, they are sometimes excessively caused or continue without any reason for providing evident benefit under certain situations or in certain diseases [Goodman & Gilman, Pharmacological Basis of Therapeutics, 9th edition, p. 827, 1999 (Hirokawa Shoten)]. The condition of living body referred to in this specification wherein an acute or chronic inflammatory reaction is observed means a condition that an excessive or unbeneficial acute or temporary inflammatory reaction or chronic and persistent inflammatory reaction is caused. Further, an inflammatory reaction-refers to a series of events caused by stimuli, for example, physical hazards such as heat, infective substances, ischemia, antigen/antibody reaction and the like, and it is accompanied by flare, swelling, hyperalgesia, algesic onset and the like as well-known macroscopic clinical symptoms. It is known that, as histological mechanisms for these reactions, vasodilation, enhancement of vascular permeability, infiltration of leucocytes and phagocytes, histological decomposition and fibrosing and the like are caused [Goodman & Gilman, Pharmacological Basis of Therapeutics, 9th edition, p. 827, 1999 (Hirokawa Shoten)]. It is known that many of these histological reactions are caused by prostaglandins and/or leukotrienes, and prostaglandins and/or leukotrienes plays important roles in inflammatory reactions.
For example, it was reported that, in a pathological tissue of rheumatoid arthritis, which is an autoimmune and chronic inflammatory disease, expression of COX-2 and production of PGE2 and TXA2 as well as expression of 5-LO and production of LTB4 were observed (Bonnet et al., Prostaglandins, 1995, vol. 50, p. 127), and in a mouse deficient in FLAP, which is a protein required for activation of 5-LO, symptom of collagen-induced arthritis, which is a pathological model of chronic rheumatoid arthritis, was milder compared with that in a wild-type mouse (Griffiths et al., J. Exp. Med., 1997, vol. 185, p. 1123), and thus it has been suggested that prostaglandins and leukotrienes play important roles in the pathological formation of chronic rheumatoid arthritis.
It was reported that, in a pathological tissue of bronchial asthma, one of chronic allergic diseases, excessive production of PGD2 and TXA2 as well as excessive production of LTC4 and LTD4 were observed (Wenzel et al., Am Rev. Respir. Dis., 1990, vol. 142, p. 112), and an airway hypersensitive reaction, which is a pathological model of bronchial asthma, was unlikely to occur in a PGD2 receptor-deficient mouse (Matsuoka et al., SCIENCE, vol. 287, p. 2013, 2000). Thus, it has been demonstrated that roles of prostaglandins and leukotrienes are important in bronchial asthma.
In a cerebral tissue after ischemic reperfusion, expression of COX-2 increased, and concentrations of PGE2 and TXA2 increased, whereas activity of 5-LO increased, and production amount of LTC4 increased (Ohtsuki et al., Am. J. Physiol., 1995, vol. 268, p. 1249). Thus, it is known that prostaglandins and leukotrienes play important roles in formation of infarct that is accepted as an ischemic reperfusion injury.
It has been revealed that, in a pathological tissue of Alzheimer's disease, one of the diseases with neurodegeneration, the COX activity and 5-LO activity increased, prostaglandins and leukotrienes cause formation of the β-amyloid protein, one of the pathogenic substances of Alzheimer's disease, and further cause degeneration of nerve cells (Sugaya et al., Jpn. J. Pharmacol., 2000, vol. 82, p. 85), and thus it is believed that prostaglandins and leukotrienes play important roles in the formation of neurodegenerative diseases such as Alzheimer's disease.
Furthermore, for example, it was reported that, in a pathological tissue of colon cancer, COX and 5-LO were expressed, and amounts of production of prostaglandins and leukotrienes were increased (Dreyling et al., Biochim. Biophys. Acta., 1986, vol. 878, p. 184), and leukotriene caused increase in colon cancer cells (Qiao et al., Biochim. Biophys. Acta, 1995, vol. 1258, p. 215; Hong et al., Cancer Res., 1999, vol. 59, p. 2223). Thus, it is believed that prostaglandins and leukotrienes play important roles also in tissues of large bowel cancer.
Involvement of prostaglandins and/or leukotrienes in diseases and pathological conditions is not limited to those diseases exemplified above, and it has been demonstrated that prostaglandins and/or leukotrienes are involved in variety of conditions, various diseases, or various pathological conditions where acute or chronic inflammatory reactions are observed and their roles are important.
For the above reason, various prostaglandin production suppressors or leukotriene production suppressors are used as agents for prophylactic or therapeutic treatment of conditions, various diseases or pathological conditions where an acute or chronic inflammatory reaction is recognized. Various non-steroidal anti-inflammatory drugs (NSAIDS) as medicaments having a prostaglandin production-suppressing action are available and used as therapeutic agents for chronic rheumatoid arthritis and osteoarthritis, antiphlogistic-analgesic agents for injury and the like, prophylactic agents for cerebral infarction or myocardial infarction, prophylactic agents for colon polyposis and the like. However, the class of NSAIDS suppress only production of prostaglandins, and as a result, they increase amounts of production of leukotrienes, and exhibit side effects such as asthmatic attack and gastrointestinal injury as well as renal disturbance. Furthermore, a difference between an effective dose and a dose inducing the side effects is small in these NSAIDS, and no satisfactory agent is available from a viewpoint of therapeutic effect. A 5-LO inhibitor is available which is described in European Patent No. 279263 as a medicament having a leukotriene production-suppressing action, and the inhibitor is known as a prophylactic agent for asthma. However, since the agent causes side effects such as hepatic disorder, its dosage is limited, and the agent is not satisfactory also from a viewpoint of therapeutic effect. Since steroid agents suppress production of both of prostaglandins and leukotrienes, they are used as prophylactic agents or therapeutic agents for conditions of living bodies, various diseases and pathological conditions where various acute or chronic inflammatory reactions are observed. However, their actions are not limited to the lipid mediator production-suppressing action, and they exhibit severe side effects such as induction and exacerbation of infectious diseases due to the immunosuppression action, growth retardation due to normal cell antiproliferative activity, anetoderma and peptic ulcer. Therefore, their uses are limited.
Furthermore, for the above reasons, it is considered that compounds, that suppress the production of both of prostaglandins and leukotrienes and have reduced side effect, are effective as therapeutic agents or prophylactic agents for such conditions of living bodies, diseases or pathological conditions in mammals as described above, and methods of using such compounds together with medicaments available at present are more effective therapeutic or prophylactic methods. Therefore, development of compounds suppressing the production of both of prostaglandins and leukotrienes, and manufacture of pharmaceutical preparations thereof are strongly desired.
As compounds structurally similar to the compounds of the present invention, for example, biphenyl-5-alkanoic acid derivatives and use thereof are described in WO99/19291. However, the moiety of these compounds that corresponds to “AR” included in the formula (I) of the compounds of the present invention is phenyl group, and thus structural features of the above compounds are different. Further, biaryl phospholipase A2 inhibitors are described in U.S. Pat. No. 5,391,817 [Japanese Patent Unexamined Publication (Kokai) No. 7-22399]. However, the moiety of these compounds that corresponds to “AR” included in the formula (I) of the compounds of the present invention is only defined to be phenyl group, and thus the structural features of the above compounds are different. Bicyclic heterocyclic compounds are described in WO00/35886 as protease inhibitors. However, the substituents of these compounds on the moiety that corresponds to “AR” included in the formula (I) of the compounds of the present invention are different, and further, the publication is completely silent about whether or not the compounds described in the above patent document have any prostaglandin production-suppressing action or leukotriene production-suppressing action.    [Patent document 1] WO99/19291    [Patent document 2] U.S. Pat. No. 5,391,817    [Patent document 3] WO00/35886